Treating haematologic malignancies upfront with a combination of drugs based on the vulnerabilities of tumours as they evolve may be a viable strategy to avoid drug resistance, according to data presented at the American Association for Cancer Research (AACR) special conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

“Our goal is to identify vulnerabilities in cancer across stages of tumour evolution while it is developing resistance to initial treatment, to help guide the design of drug combination strategies,” said Douglas Lauffenburger, PhD, professor in the Department of Biological Engineering and Koch Institute for Integrative Cancer Research at MIT in Boston.

“There may be many stages in a tumour evolution while under treatment that may make them vulnerable to already existing therapies,” Lauffenburger continued.

“Rather than waiting for the tumour to become resistant to the first treatment and then thinking about a second-line drug to use, we can capitalise on opportunities that exploit vulnerabilities at different early stages, as the tumour is evolving to become resistant to the first drug.”

In an initial screening experiment using a combination of computational and experimental approaches, Lauffenburger and colleagues Boyang Zhao and Michael Hemann identified drugs that are likely to be effective against a murine acute lymphoblastic leukaemia (ALL) cell line as the cells evolve.

These drugs were effective against certain human chronic myelogenous leukaemia (CML) cell lines as well.

Next, to develop drug combinations based on the characteristics of evolving tumours, the researchers used escalating doses of the drugs imatinib, dasatinib, nilotinib, foretinib, and crizotinib on ALL cells.

As some cells exhibited resistance to a particular drug, the research team treated the resistant cells with other drugs to check for cross-resistance.

They found that resistant cells surviving at low multiples of the original drug dose actually demonstrated sensitisation to certain other drugs, with the sensitisation abrogated at higher doses.

“Instead of only looking for the most resistant population of ALL cells at the end of this selection process, we monitored for drug sensitivity of the cells at each stage of the dose escalation,” explained Lauffenburger.

“This led us to discover the vulnerabilities of a tumour at different stages of clonal evolution, a phenomenon we would have missed if we only analysed for drug sensitivity at the last stage of this process, which is equivalent to when a patient has relapsed.

“From our studies, we found that, for example, it would be ideal to treat an ALL patient with dasatinib followed by crizotinib/foretinib for synergy during the early stages of clonal evolution of the patient’s tumour, rather than treating only with dasatinib and waiting until the patient has relapsed,” said Lauffenburger.

Source: AACR